Considerable progress has been made in our understanding of the pathophysiology of coronary artery disease (CAD); however, the genetic and molecular determinants that predispose to enhanced risk for cardiovascular disease remain poorly defined. The primary goal of this Research Program is to identify genetic and molecular determinants that participate in the development of CAD and its major complication - acute myocardial infarction (MI). To achieve this goal, our close-knit, multidisciplinary, and fully integrated team will employ a combination of clinical and translational studies that draw upon our institution's strength in cardiovascular patient care. The Research Program is structured into 4 interrelated Projects and 5 Cores that serve the Projects, including a Clinical Core built around a family based (GeneQuest) and a population based (GeneBank) clinical cohort. The goals of Project 1 are to identify and characterize genes that lead to premature CAD/MI. Preliminary data include the discovery, from a single extended pedigree, of a functional mutation in the MEF2A gene that is linked to autosomal dominantly inherited CAD, and the identification of a locus on chromosome 1 that is linked to premature MI (LOD score >11), from a genome-wide scan of 428 multiplex families with premature CAD. We propose to characterize this specific mutation, assemble more rich pedigrees, and identify additional genes that predispose to CAD/MI. The goals of Project 2 are to identify the genes responsible for the differences in atherosclerosis susceptibility among inbred strains of mice, and to determine if genetic variation in the human orthologs of these genes are associated with CAD. Preliminary data include murine atherosclerosis susceptibility loci identified through an in silico method, and gene array studies that suggest candidate genes within these loci. The goals of Project 3, originating from our novel finding of thrombospondin (THBS) variants associated with MI, are to characterize the cellular, molecular and structural consequences of 2 common variants in THBS-4 and THBS-2; and, the assessment of the consequences of these THBS variants in patients. The goals of Project 4, based upon extensive prior work in myeloperoxidase and NO-derived oxidants linked to atherosclerotic disease, are to investigate the of implications of oxidant stress, reverse cholesterol transport, and newly identified interconnections between these pathways on coronary atherosclerotic progression/regression in patients. The 5 Cores that support these projects are for 1) Administration, 2) Bioinformatics and biostatistics, 3) Gene expression, sequencing and genotyping, 4) Clinical infrastructure, and 5) Clinical research skills and development. The output from our collective work should have a significant impact on prevention, diagnosis and treatment of coronary artery disease in the future.